Molecular and Clinical Aspects of Angelman Syndrome

Abstract

The Angelman syndrome is caused by disruption of the UBE3A gene and is clinically delineated by the combination of severe mental disability, seizures, absent speech, hypermotoric and ataxic movements, and certain remarkable behaviors. Those with the syndrome have a predisposition toward apparent happiness and paroxysms of laughter, and this finding helps distinguish Angelman syndrome from other conditions involving severe developmental handicap. Accurate diagnosis rests on a combination of clinical criteria and molecular and/or cytogenetic testing. Analysis of parent-specific DNA methylation imprints in the critical 15q11.2-q13 genomic region identifies 75-80% of all individuals with the syndrome, including those with cytogenetic deletions, imprinting center defects and paternal uniparental disomy. In the remaining group, UBE3A sequence analysis identifies an additional percentage of patients, but 5-10% will remain who appear to have the major clinical phenotypic features but do not have any identifiable genetic abnormalities. Genetic counseling for recurrence risk is complicated because multiple genetic mechanisms can disrupt the UBE3A gene, and there is also a unique inheritance pattern associated with UBE3A imprinting. Angelman syndrome is a prototypical developmental syndrome due to its remarkable behavioral phenotype and because UBE3A is so crucial to normal synaptic function and neural plasticity.

Fig. 1

Pictured are individuals who have genetic test-proven Angelman syndrome. The mechanisms identified in them are: 15q11.2–q13 deletion (A, B, D, E); paternal uniparental disomy (C); UBE3A mutation (F, G) and imprinting defect (H). Individuals A, B and C illustrate some of the gait characteristics seen in the syndrome. Protruding tongue can be a noteworthy phenotypic feature, especially in combination with laughter (as in C), but most do not have pronounced tongue protrusion. The girl H has a non-deletion, mosaic-type imprinting defect, and thus her cognitive and language skills are relatively higher than observed in the typical child with the syndrome.

Fig. 2

Schematic diagram of the UBE3A gene showing exons 1–16 and 3 of the most studied protein isoforms that differ by 20 and 23 amino acids at the amino terminal aspect. Exons 9–16 constitute the HECT binding and transfer domains. The steroid coactivation region does occupy a contiguous genomic region but spans a region that contains several 5-amino acid motifs known to be receptor interacting motifs [Ramamoorthy and Nawaz, 2008]. An alternative exon numbering system for UBE3A is indicated by the asterisk, as designated by Yamamoto et al. [1997].

Fig. 3

Schematic drawing of chromosome region 15q11.2–q13 indicating the breakpoint regions BP1–BP6. Low-copy repeat elements are located within these breakpoint regions (see text for details). Approximately 90% of chromosome deletions resulting in Angelman syndrome initiate at BP1 or BP2 and terminate in region BP3 (class I and class II). Approximately 10% of deletions are larger, typically spanning from BP1 to BP5, rarely beyond BP5. Genes that are not imprinted and thus biparentally expressed are noted by the open circles. The 2 critical imprinting center (IC) elements, the AS-SRO and the PWS-SRO, are drawn as open boxes. The shaded box for the SNURF-SNRPN gene is shown with some overlap with the PWS-SRO. The SNURF-SNRPN sense/UBE3A antisense transcript is labeled UBE3A-AS. Distances are not to scale particularly between SNRPN and UBE3A; not pictured are the paternally expressed snoRNAs that are transcribed as part of the long antisense transcript between these 2 genes.